Mode of Action of Antidepressant Drugs — Primary Effects

Abstract

The primary effects of the majority of today’s antidepressants relate to their ability to increase the availability of the synaptic concentration of the catechol and/or indolamine transmitters by preventing their neuronal reuptake or metabolic deamination via MAO. The clinical antidepressant efficacy, however, does not seem to be determined either by the potency of amine-uptake inhibition or MAO inhibition, nor by the selectivity of action of a drug on one particular monoaminergic system. Moreover, neither of these effects is necessarily a prerequisite for the therapeutic action of drugs in depression. There is also no obvious causal relationship between the primary action of drugs on various postsynaptic receptor sites and their antidepressant potential. Direct blocking effects on a1 adrenoceptors, muscarinic and histaminergic receptors, however, appear to relate to certain clinical side effects of these drugs. Nevertheless, even though the primary effects of antidepressants cannot be always reconciled with the monoamine hypothesis of depression, ultimately they may be of importance in determining the long-term changes of the transmission in monoaminergic neurons.